Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis

Abstract

Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8 + T cell axis accompanied by interferon-g and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification. Furthermore, urinary TLS signature scores correlated with ICI-AIN diagnosis but not paired plasma. Urinary CXCL9 correlated best to tissue CXCL9 expression (rho 0.75, p < 0.001) and the ability to discriminate AIN vs. non-AIN (AUC 0.781, p-value 0.003). For the first time, we report the presence of TLS signatures in irAEs, define distinctive immune signatures, identify chemokine markers distinguishing ICI-AIN from common AKI etiologies and demonstrate that urine chemokine markers may be used as a surrogate for ICI-AIN diagnoses.

The roles of tertiary lymphoid structures in chronic diseases

“…Kidney. TLSs can be induced in CKDs, including IgA nephropathy [158][159][160] , lupus nephritis 65 , IgG4-related kidney diseases 161 , interstitial nephritis 162,163 , membranous nephropathy 164 and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis 165,166 as well as in kidney allografts 37,39,44,[167][168][169][170] . Clinical studies have demonstrated that TLS formation is associated with poor kidney outcomes in these diseases (Supplementary Table 2).…”

Effects of immune‐related adverse events (irAEs) and their treatment on antitumor immune responses

“…As our understanding of irAE mechanisms in patients evolve, it will help to identify which, if any, animal models most accurately recapitulate organ-specific irAEs in patients and inform the next generation of irAE models that can be used to test the relationship between irAE therapeutics and antitumor efficacy. 53 As T cells are thought to be central to the antitumor responses driven by ICIs 4,9 and are found to predominate the immune cell infiltrate in irAE tissue biopsies across organ systems, 8,10,11,13,16,23,38,[54][55][56][57] many studies have looked at the relationship of T cells in irAEs and paired tumors. While central and peripheral tolerance mechanisms cause many autoreactive T cells to become anergic or die during Tcell development, autoreactive T cells are still commonly found in humans 14,44 and are anticipated to play a role in the development of irAEs.…”

“…69 B cells, particularly in the formation of tertiary lymphoid structures, have been found to play a role in antitumor responses 70 as well as irNephritis. 13 The emerging role of B cells in antitumor immunity suggests that interventions to mitigate antibody-mediated irAEs could have negative consequences for tumor immunity.…”

“…The CXCL9/10/11 chemokine system has been implicated across irAEs 72 and specifically in irMyocarditis, 73 irColitis, 11 irArthritis, 12 and irNephritis. 13 However, this chemokine system is involved in the recruitment of lymphocytes and other immune cell into tumors, and this signaling is thought to be necessary for antitumor immunity. 74 IL-17 has been associated with severe irColitis and irDermatitis, 75 but treatment of an irAE with an IL-17 inhibitor has also been seen to cause a loss of tumor control.…”

“…6,7 While the prevailing hypothesis in the field suggests that irAEs are due to a loss of self-tolerance, 8,9 the mechanistic drivers of irAEs are only beginning to emerge. [10][11][12][13][14][15][16] As murine tumor models typically utilized to study ICI efficacy do not develop severe irAEs, 17 insights into the relationship between irAEs and antitumor immunity have been guided by clinical observations and translational research. Currently, the management of severe irAEs involves discontinuing ICI therapy and administering glucocorticoids and other immunosuppressive medications, [18][19][20][21] which may adversely impact antitumor immunity.…”